All about Drugs, live, by DR ANTHONY MELVIN CRASTO, Worlddrugtracker, OPEN SUPERSTAR Helping millions, 9 million hits on google, pushing boundaries,2.5 lakh plus connections worldwide, 22 lakh plus VIEWS on this blog in 220 countries, 7 CONTINENTS The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent, USE CTRL AND+ KEY TO ENLARGE BLOG VIEW……………………A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, With death on the horizon, I have lot to acheive

It is believed to work in the brain and spinal cord to relieve pain. There it is believed to work via rather unique mechanisms. Firstly it increases the activity of the serotonin, norepinephrine and dopamine, neurotransmitters involved in, among other things, pain signaling. Secondly, it modulates sodium and calcium channels, thereby inhibiting the release of glutamate, a key neurotransmitter involved in pain processing.[4

Medical uses

Nefopam has additional action in the prevention of shivering, which may be a side effect of other drugs used in surgery.[5] Nefopam was significantly more effective than aspirin as an analgesic in one clinical trial,[6] although with a greater incidence of side effects such as sweating, dizziness and nausea, especially at higher doses.[7][8] Nefopam is around a third to half the potency and slightly less effective as an analgesic compared to morphine,[9][10][11] or oxycodone,[12] but tends to produce fewer side effects, does not produce respiratory depression,[13] and has much less abuse potential, and so is useful either as an alternative to opioids, or as an adjunctive treatment for use alongside opioid(s) or other analgesics.[11][14] Nefopam is also used to treat severe hiccups.[15]

Side effects

Common side effects include nausea, nervousness, dry mouth, light-headedness and urinary retention.[16] Less common side effects include vomiting, blurred vision, drowsiness, sweating, insomnia, headache, confusion, hallucinations, tachycardia, aggravation of angina and rarely a temporary and benign pink discolouration of the skin or erythema multiforme.[16]

Society and culture

Recreational use

Recreational use of nefopam has been reported,[17] although this is less common than with opioid analgesics.[18]

SYNTHESIS

PATENT

ES 8605495

The reaction of 2-benzoylbenzoic acid (I) with SOCl2 in CHCl3, benzene or DMF gives the corresponding acyl chloride (II), which is condensed with ethanolamine (III) by means of TEA in CHCl3 to yield the amide (IV). The reduction of (IV) with LiAlH4 in THF affords the diol (V), which is cyclized by means of Ts-OH in refluxing benzene to provide 1-phenyl-3,4,5,6-tetrahydro-1H-2,5-benzoxazocine (VI). Finally, this compound is methylated by means of dimethyl sulfate in refluxing benzene, or by means of formaldehyde in hot dioxane/water. Alternatively, the cyclization of N-[2-[1-[2-(chloromethyl)phenyl]-1-phenylmethoxy]ethyl]-N-methylamine (VII) by means of pyridine in refluxing acetonitrile gives also the target benzoxazocine

PATENT

KE 8201564

PATENT

ES 8104800

The reaction of 3-phenylphthalide (I) with N-methylethanolamine (II) in refluxing benzene gives N-(2-hydroxyethyl)-2-(1-hydroxy-1-phenylmethyl)-N-methylbenzamide (III), which is cyclized by means of Ts-OH in refluxing toluene to yield 5-methyl-1-phenyl-3,4,5,6-tetrahydro-1H-2,5-benzoxazocin-6-one (IV). Finally this compound is reduced with LiAlH4 in refluxing THF to afford the target benzoxazocine. In an alternative method, the reduction of 2-benzoyl-N-(2-hydroxyethyl)-N-methylbenzamide (V) by means of sodium bis(2-methoxyethoxy)aluminum hydride in refluxing toluene gives the diol (VI), which is then cyclized by means of Ts-OH in refluxing toluene, or by means of aq. 48% HBr in hot chloroform to afford the target benzoxazocine

The reaction of 2-benzoylbenzoic acid (I) with refluxing SOCl2 gives the corresponding acyl chloride (II), which is condensed with 2-(methylamino)acetic acid (III) in benzene to yield the N-(2-benzoylbenzoyl)-N-methylglycine (IV). The reduction of (IV) by means of LiAlH4 in refluxing THF affords the diol (V), which is finally cyclized by means of PPA at 80 C to provide the target benzoxazocine.

This compound is useful as an intermediate in producing the pharmacologically valuable 3,4,5,6-tetrahydro-5-methyl-l-phenyl-lH-2,5-benzoxazocine- hydrochloride, or nefopam, which is used, e.g. as a muscle relaxant, an analgesic or antidepressant drug.

Processes for producing the compound of formula I are already known. For instance, according to German Patent 1,620,198, phthalic aldehyde is used as a starting material. According to the German Patent, the phthalic aldehyde is reacted with a Grignard reagent, phenylmagnesiumbromide, and an N-substituted aminoalcohol is coupled to the reaction mixture, to produce a product of formula:

This product is catalytically hydrogenated with the aid of Pd/C, Pt or Raney-Ni, and a product of formula I is obtained.

In another method, according to the German Patent 1,620,198, o-benzoylbenzoic acid is used as a starting material, which is converted by means of thionylchloride into an acid chloride. To this acid chloride is then coupled methylethanolamine, and N-(2-hydroxyethyl)-N-methyl-o-benzoylbenzamide is obtained as an intermediate, which is reduced using LiAlH4 and an end-product of formula I is produced.

According to United States Patent 3,487,153 o-benzoylbenzoic acid amide is used as starting material to produce the intermediate. With the aid of thionylchloride the corresponding acid chloride is formed, which is allowed to react with N-methyl-2-aminoethanol. The so-produced N-(2-hydroxyethyl)-N-methyl-o-benzoylbenzamide is reduced with LiAlH4 to 2{[N-(2-hydroxyethyl)-N-methyl)amino}-methylbenzhydrol.

According to German Offenlegungschrift 2,834,312 o-benzoylbenzoic acid is used as a starting material, which is allowed to react with phosphorus trichloride in dichloroethane. The acid chloride formed is allowed to react with triethylamine and N-methyl-2-hydroxyethyl- amine, after which N-(2-hydroxyethyl)-N-methyl-o-benzoylbenzamide is formed. This compound is treated with phosphorus trichloride (at pH=7.0) and N-(2-chloroethyl)-N-methyl-o-benzoylbenzoic amide is obtained, which is then reduced with NaBH4 in acetic acid. By these means 2-{[N-(2-hydroxyethyl)-N-methyl]-amino?-methylbenzhydrol is obtained.

According to Finnish Patent No. 54793, which corresponds to Canadian Patent 982,608, a compound of formula III is used as starting material, which is reduced with NaBH4 to a corresponding benzhydrol derivative of formula IV, which is then allowed to react with an alkylamine to an a-substituted 2-aminomethyl- benzylalcohol of formula V. The abovementioned Patent does not concern either the preparation of nefopam or its intermediates

When reviewing the abovementioned Patents, i.e. German Patent 1,620,198 and United States Patent 3,487,153, one can observe the disadvantage that catalytic hydrogenation with palladium on charcoal, platinum or Raney-Ni, or lithium aluminium hydride are to be used to reduce the starting materials. This latter reagent is expensive and reacts with water very intensely, so that even a little humidity in the working surroundings or in the solvents can cause a fire. Explosive hydrogen is also produced by the reaction. Grignard reactions and catalytic hydrogenations are technically difficult to perform on a large scale. Moreover, the price of o-phthalic aldehyde is high.

According to the method described in German Offenlegungschrift 2,834,312 the reducing of the amide- carbonyl group with sodium borohydride in acetic acid requires, however, great additional amounts or about 2-3 equivalents of sodium borohydride. The yield of the reaction is quite poor (about 50-55%) and the reaction time is long, so the production costs become high. Moreover, the number of synthetic reaction steps is high and the use of phosphorus trichloride especially on a production scale is difficult.

In the method according to the Finnish Patent 54793, which corresponds to the Canadian Patent 982,608, a benzophenone derivative (of formula III) is reduced with NaBH4 to the corresponding benzhydrol derivative (formula IV). This compound is, however, unstable because of the methylene halogen group in o-position, especially when R1 = H in formula IV. On storing for only a short time hydrogenchloride gas is released and a very stable 5-ring ether is formed, which is useless. The use of this method on a large scale is therefore almost impossible, because the intermediate is impossible to isolate fast enough to obtain at least a reasonable amount of the end product.

The present invention provides a process for the preparation of 2-{[N-(2-hydroxyethyl)-N-methyl]-amino}-methylbenzhydrol (as such or as an acid addition salt) which comprises reacting 2-chloromethylbenzophenone with 2-methylaminoethanol to give 2-J[N-(2-hydroxyethyl)-N-methyl]-amino}-methylbenzophenone (as such or as a salt), and reducing the latter with sodium borohydride to give 2-{[N-2-(hydroxyethyl)-N-methyl)-aminol}-methylbenzhydrol (as such or as an acid addition salt). The 2-chlorobenzophenone (of formula VI) is brought to react with methylethanolamine in the presence of e.g. sodium carbonate, and 2-{[N-(2-hydroxyethyl)-N-methyl]-amino}- methylbenzophenone (of formula VII) is formed. This substance is theoreduced with sodium borohydride to 2-{(N-(hydroxyethyl)-N-methyl]-amino}-methylbenzhydrol (of formula VIII), as shown below:

The starting material, 2-chloromethyl benzophenone, can be produced in known manner by halogenating the corresponding 2-methylbenzophenone (Monatshefte far Chemie 99, 1990-2003, 1968) or 2-hydroxymethylbenzophenone, of which the former is commercially available and the latter can be produced in known manner from the phthalide (see British Patent 1,526,331). The compound of formula VII is new, and as such a feature of the invention.

The following Examples illustrate the invention.

EXAMPLE 1

8.50 g (0.037 mol) 2-chloromethylbenzophenone is dissolved in 40 ml ethylalcohol, and 4.0 g sodium carbonate and 2.80 g (0.037 mol) 2-methylaminoethanol are added, The mixture is boiled for 3 hours and the salts formed are filtered off from the cooled solution. A pure reaction product is obtained when the ethanol is evaporated from the solution and the product is crystallized as a hydrochloride salt from a mixture of diethylether and alcohol. The yield is 10.7 g (95 %) of 2{(N-(2-hydroxyethyl)-N-methyl]-amino}- methylbenzophenone as a crystalline powder, m.p. 135-136 C.

10.0 g (0.033 mol) of the hydrochloride salt prepared in Example 1 are dissolved in a mixture comprising 15 ml water, 60 ml methanol and 3.5 g sodium hydroxide. To the mixture is added 0.65 g sodium borohydride and the solution is mixed for half an hour at room temperature.

The solution is acidified with concentrated hydrochloric acid and the methanol is evaporated in vacum. 40 ml of water is added, the pH of the water solution is adjusted with diluted sodium hydroxide solution to an alkaline reaction and the product is extracted into chloroform. The chloroform extracts are washed well with water, dried over sodium sulphate and evaporated to dryness. The product is separated by precipitating as a hydrochloride salt from a mixture of diethylether and ethylalcohol. The yield is 9.8 g (96 %) of 2-{(N-(2-hydroxyethyl)-N-methyl]-amino}- methylbenzhydrol as a crystalline powder, m.p. 128-133 C.

[0045] B in the amine solution and then dropping phosphorus trichloride 33g, reaction at 65 ° C 2h, washed with water cooling, the solution was washed with a dilute solution of sodium hydroxide, to sub-alkaline layer chloride solution C.

[0046] In the reaction flask was added a certain amount of potassium borohydride; potassium borohydride to mass, and then the mixture was added 15% acetic acid and dichloroethane (solvent of acetic acid mass ratio of 1: 1); to potassium borohydride mass, and then added dropwise to obtain 45% of the chlorination reaction chloride solution C, stirring the reaction was heated to reflux for 2h, pre-reduction; with potassium borohydride mass, further addition of 10% acetic acid and dichloroacetyl alkane mixture (mass ratio of acetic acid to solvent is 1: 1), the reaction was stirred Ih; in reducing mass, and finally the mixture was added dropwise 45% obtained by chlorinating liquid the chlorination reaction C with acetic acid (chloride quality liquid C and acetic acid ratio of 1: 1), the reaction was stirred tank for the final reduction.Plus 40% hydrolyzed sodium hydroxide solution, the organic layer was separated D

[0052] B in the amine solution and then dropping phosphorus trichloride 33g, reaction at 65 ° C 2h, washed with water cooling, the solution was washed with a dilute solution of sodium hydroxide, to sub-alkaline layer chloride solution C.

[0053] In the reaction flask was added a certain amount of potassium borohydride; potassium borohydride to mass, and then the mixture was added 25% acetic acid and dichloroethane (solvent of acetic acid mass ratio of 1: 1); to potassium borohydride mass, then dropping to 50% of the chlorination reaction chloride solution C, stirring heated to reflux for 2h, pre-reduction; potassium borohydride mass, then add 20% acetic acid and dichloroethane alkane mixture (mass ratio of acetic acid to solvent is 1: 1), the reaction was stirred Ih; in reducing mass, and finally the mixture was added dropwise a 50% solution chlorination reaction C and obtained by chlorinating acetic acid (chloride quality liquid C and acetic acid ratio of 1: 1), the reaction was stirred tank for the final reduction.Plus 40% hydrolyzed sodium hydroxide solution, the organic layer was separated D

[0054] The separated organic layer D was cooled to room temperature and added slowly with stirring at 65 ° C the reaction hydrobromide 8h, the reaction is completed, cooled to 0 ° C, and filtered to give the cyclization product E.

[0055] The cyclization to give the reaction product E was added sodium hydroxide solution and then dropwise addition of concentrated hydrochloric acid, to obtain Nefopam.

[0056] The applicant stated the above embodiments of the present invention will be described in detail the process equipment and process of the present invention, but the invention is not limited to the above detailed process equipment and process, that does not mean that the present invention must rely on such details process equipment and processes to be implemented.Skill in the art should be appreciated that any improvement in the present invention, the present invention is the product of the raw materials equivalents and adding auxiliary components, choice of specific ways, and fall within the scope of the public of the scope of the present invention.

Nefopam hydrochloride is extensively used in most of the European countries until today as an analgesic because of its non-opiate (non-narcotic) and non-steroidal action with fewer side effects compared with opioid and other analgesics, which cause more troublesome side effects. A multikilogram synthesis of nefopam hydrochloride has been achieved in one pot using a single solvent (toluene). A ≥99.9% purity of the active pharmaceutical ingredient (API) was achieved in excellent overall yield (≥79%). The one-pot, five-step synthetic process involves formation of an acid chloride (3) from benzoylbenzoic acid (2) followed by amidation (4), reduction (5), cyclization (6), and formation of the hydrochloride salt (1). The major advantages include (i) use of a single solvent, (ii) >90% conversion in each step, (iii) a cost-effective and operationally friendly process, (iv) averting the formation of genotoxic impurities, and (v) improved overall yield (≥79%) provided by the one-pot operation. For the first time, we report the characterization data of API 1, intermediates 3, 4, and 5, and also a possible impurity (5a).

Jump up^Roth, BL; Driscol, J. “PDSP Ki Database”. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.

DISCLAIMER

“DRUG APPROVALS INT” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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